Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Pathologic differentiation between HCC from metastatic carcinoma and cholangiocarcinoma has critical therapeutic implications. However, it is occasionally challenging and sometimes requires immunohistochemical panels. Recently, Arginase- 1, MOC-31, and CDX2 have been introduced for the differentiation of these tumors. This study was conducted to determine the value of expression of Arginase-1, MOC- 31, and CDX2 in differentiating primary carcinoma of the liver from cholangiocarcinoma and metastatic adenocarcinoma to the liver. Methods: 50 cases of HCC, 20 cases of metastatic colonic carcinoma to the liver, and 10 cases of cholangiocarcinoma were evaluated for immunohistochemical expression of Arginase-1, MOC-31, and CDX2. Results: Arginase-1 was positive in 45 (90%) of HCC cases and negative in metastatic carcinoma and cholangiocarcinoma cases. MOC-31 was positive in 19 (95%) of metastatic colonic adenocarcinoma cases and 10 (100%) of cholangiocarcinoma cases, while it was negative in HCC cases. CDX2 was positive in 18 (90%) of metastatic carcinoma cases while it was negative in cholangiocarcinoma cases. The sensitivity of Arginase-1 for HCC, MOC-31 for MC, and CDX2 for metastatic colonic carcinoma in the studied groups was 95%, 100%, and 98%, respectively, whereas its specificity was 100%, 96.7%, and 60%, respectively. The difference of Arginase-1, MOC- 31, and CDX2 expressions in HCC, cholangiocarcinoma, and metastatic colonic adenocarcinoma were statistically significant (P<0.001). Conclusion: Our study revealed that Arginase-1, MOC-31, and CDX2 expression are suitable IHC markers in the differential diagnosis of HCC, cholangiocarcinoma, and metastatic colonic adenocarcinoma.